Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is prevalent in critically ill people and is associated with a poor prognosis for survival in patients with sepsis and septic shock. However, the likelihood of death can be significantly reduced if these patients are supplemented with the synthetic cortisol product, hydrocortisone. Preliminary work in our laboratory suggests that HPA axis dysfunction is as prevalent and has the same negative impact on survival in neonatal foals presented to veterinary teaching hospitals with sepsis. Thus, neonatal foals with naturally-occurring diseases that result in sepsis appear to be excellent model for investigation of HPA axis dysfunction in critically ill humans, and provide insight that may benefit both human and veterinary medicine. In the proposed study, we will use septic neonatal foals to investigate a potential mechanism for HPA axis dysfunction in critical illness, and to evaluate the efficacy of low-dose hydrocortisone replacement therapy in sepsis in a multi-center double-blinded placebocontrolled study. This will be accomplished by completing three major objectives: 1) the daily endogenous cortisol production rate and hydrocortisone pharmacokinetics will be determined in healthy foals to determine an appropriate hydrocortisone replacement regimen;2) this hydrocortisone dose will be given to healthy newborn foals and ex vivo measures of innate immunity will be assessed before, during, and after treatment to ensure the proposed regimen modulates but does not eliminate the inflammatory response;and 3) a multi-center, double-blind, placebo-controlled study will be conducted to determine the efficacy of hydrocortisone replacement therapy at modulating inflammation and reducing disease severity and death in septic foals. This study includes a multi-disciplinary approach that is relevant to the NIH missions of training clinician scientists, advancing disease diagnosis and treatment (NIGMS) and the control of infectious and immunological disease (NIAID) that is accompanied by endocrine dysfunction (NIDDK) during the neonatal period (NICHD). This proposal has enormous public health relevance, as it will investigate a high profile hormonal disorder that affects approximately half of all people with serious infection.